In silico and pharmacokinetic studies of glucomoringin from Moringa oleifera root for Alzheimer's disease like pathology

Aim: The aim of this research is to investigate the potential of glucomoringin, derived from Moringa oleifera, as a therapeutic agent for Alzheimer's disease through in silico analysis. Materials & methods: This study employs in silico or computational methodologies, including pkCSM, Swiss ADME, OSIRIS® property explorer, PASS online web resource and MOLINSPIRATION® software, to predict the pharmacokinetic characteristics and biological activity of glucomoringin. Results & conclusion: Molecular docking indicates strong binding to I-1β and the pharmacokinetic profile shows cytochrome P450 enzyme inhibition, prompting further research for dosing strategies. Toxicological predictions affirm safety, while bioactivity assessments demonstrate versatility in modulating essential pathways. glucomoringin's potential for Alzheimer's treatment, emphasizing the need for additional empirical research.


Molecular docking analysis
The crystal structures, including 1F4G, 3IG5, 3E0U, 15EA, 6FN8, 5IKR, 1ITB, 1ALU, 1NFK and 2AZ5 were extracted from the Protein Data Bank (PDB) (http://www.rcsb.org).Subsequently, the PDB structures were refined by removing the inhibitor ligands and any other associated chains.The proteins utilized in this research were designed with the assistance of MMV and AutoDock.Following this initial design phase, a second round of enhancements was carried out on the modified proteins.This involved stabilizing the ionized and tautomeric states of the amino acid residues, necessitating the removal of water molecules and the addition of hydrogen atoms.To maintain the updated protein structure for further docking studies, a PDB file was generated.The optimization of the proteins in this study was accomplished using the Molegro molecular viewer.Adjustments to the bond order were made after the removal of water and covalently attached ligands.Charge and protonation states were assigned and the energy of the system was minimized using the molecular mechanics force field.For the molecular docking simulations, the AutoDock program was employed.This program automatically computed Gasteiger charges and assessed the ligand's rotatable bonds to generate multiple conformers for the docking process.Receptor grids were constructed based on designated receptor points and grid boxes were created using the receptor grids' axes as the domain.The macromolecule was positioned centrally within the grid.Several types of maps were generated using Autogrid 4. All molecular docking simulations were conducted using the Lamarckian genetic algorithm.The docking procedure was set to include 50 iterations, 150 subjects, 2.5 million assessments and 27,000 generations.Biovia Discovery Studio 2021 was utilized to import the docking snapshots and the resulting docked structures were exported to pdbqt format.Subsequently, Biovia Discovery Studio 2021 was employed to visualize the docking results, which revealed the presence of hydrogen and hydrophobic interactions at the inhibitor sites of the docked targets [38][39][40][41][42][43][44].

Pharmacokinetic assessment
Extracting data from the PubChem server unveiled the standard chemical structure of glucomoringin.Comprehensive pharmacokinetic investigations were carried out using pkCSM and Swiss ADME.The ADMET profile was obtained from the host computer based on canonical smiles.Both pkCSM and Swiss ADME furnish insights into the pharmacokinetics (PK), pharmacodynamics (PD) and toxicology (toxicity) of the drug.PkCSM, as a web-based application, facilitates the examination of the pharmacokinetic characteristics of pharmaceutical compounds.The pkCSM software was employed to assess glucomoringin physicochemical attributes [45,46].By evaluating their binding affinities and pharmacokinetic characteristics, we pinpointed the top-docked compounds, signifying their potential as therapeutic candidates.However, when employing effective strategies in drug design, development and discovery, it is crucial to take into account a range of critical pharmacokinetic factors and AD-MET attributes, including absorption, distribution, metabolism, excretion and toxicity.To gain insights into the physicochemical properties and ADMET attributes of the substance under examination, an extensive investigation was conducted using online web-based tools.glucomoringin underwent an analysis based on Lipinski's rule of five, which identifies five essential physicochemical features that significantly influence a molecule's effectiveness, safety and metabolism.It was observed that there were violations of LogP across all three Consensus LogPo/w implementations tested (WLOGP, XLOGP3 and LOGP).The logarithm of the partition coefficient between n-octanol and water, representing lipophilicity values between -0.7 and +5.0, was determined using atomistic and topological implementations of Moriguchi's topological approach, including XLOGP3, WLOGP and MLOGP

Toxicological modeling & simulation
In order to mitigate potential complications during the process of discontinuing a drug, which could include issues like organ system failure or damage, it is imperative to conduct toxicological assessments.The OSIRIS property explorer software was employed, utilizing PubChem structures, to assess the compounds' toxicity profiles.These substances are categorized on a color-coded scale according to their likelihood to induce cancer, mutations, irritation, reproductive effects and their potential as pharmaceutical agents.An overall drug score, a drug-likeness score and TPSA (topological polar surface area) were computed based on the following toxicity criteria: substances with high risk are denoted in red, those with medium risk are in yellow and those with low risk are depicted in green [44].

Analysis of glucomoringin biological activity
The PASS (prediction of action spectra for substances) tool was employed to predict the biological actions of the medications.It anticipates the biological activity spectrum of a drug based solely on its structural formula, relying on the correlation between structure and behavior.The capacity of a chemical compound to exhibit pharmacological or biological effects is of paramount importance, as it unveils potential applications for the compound in the field of medicine.Furthermore, the potential adverse effects of these drugs were also foreseen with the assistance of the PASS ONLINE tool.Biologically active compounds were assessed using the web-based PASS program, which has the capability to forecast over 300 distinct pharmacological activities and biological pathways.These predictions are rooted in the structural formula of the substance and they hold the potential to uncover new pharmaceutical targets based on the gathered information [47,48].

Molecular property analysis
The chosen drugs underwent in silico testing with the MOLINSPIRATION software to assess drug similarity and forecast their bioactivity.A higher score indicates an increased likelihood that the molecule in question will exhibit activity.A chemical with a bioactivity score greater than 0.00 is deemed to possess noteworthy biological properties.Scores falling within the range of -0.50 to 0.00 on the bioactivity scale are considered highly active, while values below -0.50 are categorized as inactive [49].

Molecular docking assessment of glucomoringin
To determine whether glucomoringin might directly bind to the chosen genes, a ligand binding simulator was run before the experimental study.When comparing Alzheimer's biomarkers, oxidative stress associated protein catalase, glutamate cysteine ligase, glutathione peroxidase, NADPH quinone dehydrogenase, superoxide dismutase.Other targets inflammatory receptors include COX-II, I-1β, IL-6, NF-κB, TNF-α stand out as crucial.glucomoringin showed the highest binding energy in IL1β (PDB: 1ITB = -6.77kcal/mol) which was illustrated in Figure 1.Since molecular docking persists as a computer simulation approach used for determining the shape of a receptor ligand complex, the hypothesis desires to be tested empirically in future studies, but the data presented here suggests that glucomoringin might have a significant ability to directly connect with inflammatory molecules.The glucomoringin formed a hydrogen bond with amino acid residues LYS114, GLU202, MET148, ASN204, ASN108 and GLN149 for 1ITB.Each target ligand generated at least one hydrogen bond with active chemical residues, providing confidence to the accuracy and precision of the prediction made by the investigation.The outcomes of molecular docking simulations for selective receptor binding are displayed in Table 1.In most selected targets, a considerably increased number of amino acid residues engaged in hydrogen bonding and Van der Waals interactions was related with shorter hydrogen bond lengths (less than 3.0).

Glucomoringin pharmacokinetic profile
Glucomoringin is an inhibitor of CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzyme and its clearance was calculated to be -0.018ml/min/kg.The pkCSM database shows that the maximum safe daily intake of glucomoringin in humans is 0.358 mg/kg, LD 50 was predicted to be 3750 mg/kg and the drug profile was listed in Table 2.The predicted toxicity class 5, average similarity and prediction accuracy was found to be 42.1% and 54.26%.Hepatotoxicity, carcinogenicity, mutagenicity, cytotoxicity predicted inactive but surprisingly immunotoxicity found to be active.
The chemical does not cause skin sensitivity, liver, or renal damage.It yields a favorable bioactivity score for therapeutic targets; this pharmacokinetic technique is trustworthy for use in drug development and pharmacokinetic analysis.Based on its pharmacokinetic profile, SwissADME concludes that glucomoringin has a low GI absorption and it's a p-glycoprotein I and II inhibitor.Table 3 lists the predicted ADMET properties.However, % intestinal absorption rate of 4.094% is significantly low.The permeability of glucomoringin via the blood-brain barrier was found to be -1.394(log BB).However, its central nervous system (CNS) permeability was found to be -4.061(log PS), indicating enhanced CNS penetration and the potential to exert its pharmacological effects.ADMET predictions showed that the calculated absorption properties (percent human intestinal absorption, skin permeability and BBB permeability) were not P-glycoprotein I and II inhibitors because they were below the threshold values.This demonstrates that glucomoringin has significant pharmacological properties.Glucomoringin physiochemical profile was appealing because its anticipated values were within the acceptable range.

Bioactivity score assessment of glucomoringin
The Molinspiration online tool provides free online services to the internet chemistry community, such as the prediction of bioactivity score for the most important drug targets such as GPCR ligands (0.19), ion channel modulators (-0.17), kinase inhibitors (-0.19) and nuclear receptors (-0.10) and the calculation of critical molecular properties (polar surface area, logP, number of hydrogen bond donors and acceptors and others).

Discussion
Alzheimer's disease is a neurodegenerative ailment that is incredibly widespread and has a catastrophic impact on the lives of millions of people all over the world.Despite the fact that there is now no known cure, the treatment focuses mostly on symptom control.The investigation of complementary and alternative treatments,  such as those involving herbs, to improve cognitive health has garnered a growing amount of interest.The use of precision medicine is yet another promising approach being taken in Alzheimer's research.Alzheimer's disease is not a disease that affects everyone in the same way; rather, it has a variety of underlying causes and elements that contribute to its progression.Researchers are increasingly concentrating their efforts on developing medicines that are uniquely suited to the genetic and molecular profile of the patient.This individualized strategy tries to target the fundamental causes of the disease, such as amyloid plaques and tau tangles, in order to slow down or stop the progression of the disease.Early study indicates that the plant Moringa oleifera, which is high in alkaloids, may be useful in the treatment of Alzheimer's disease.A number of these alkaloids have features that include inhibition of cholinesterase, neuroprotection, antioxidant activity and anti-inflammatory action.Herbal remedies, such as moringa, have shown some promise in the treatment of Alzheimer's disease; nonetheless, they should not be used in place of evidence-based medicinal procedures.glucomoringin has a high concentration of An analysis of molecular docking was performed on Moringa oleifera since it is of interest as a chemical.An exhaustive investigation into the potential of glucomoringin within the setting of Alzheimer's disease using in silico experiments.Strong binding to interleukin-1 (-5.77 kcal/mol) was observed, which is suggestive of the possibility of direct interaction with inflammatory molecules.Inflammation is an essential component of Alzheimer's disease.The formation of hydrogen bonds with particular amino acid residues in the target provides evidence that the interaction is particularly robust.The pharmacokinetic profile of the chemical showed that it inhibited a number of cytochrome P450 enzymes and it reported having a decent clearance rate.The predicted safety statistics revealed both the LD50 and the maximum safe daily dosage for this substance.According to the findings of toxicological studies, glucomoringin does not have any mutagenic, carcinogenic, irritating, or reproductive effects, which indicates that it could be a viable option for safe medical treatment.The drug score of 0.3 indicates that the key pharmacological qualities, such as TPSA and drug-likeness, were found to be within acceptable levels.The evaluation of glucomoringin's bioactivity revealed that it possessed a high bioactive score in a number of significant therapeutic targets.
The treatment and management of Alzheimer's disease typically involve medications such as cholinesterase inhibitors Donepezil [50][51][52] and Rivastigmine [53-56]; NMDA receptor antagonist Memantine [57-61] to manage symptoms, support from caregivers and lifestyle interventions, but there is no cure for the disease.Promising areas of research include understanding the role of inflammation and oxidative stress in the development and progression of Alzheimer's disease, but more research is needed to develop effective treatments.While the compounds found in plants like moringa, including glucomoringin [62,63], may have various health benefits and antioxidant properties, they should not be considered as a sole or primary treatment for Alzheimer's disease.If you or someone you know is concerned about Alzheimer's disease, it is important to consult a healthcare professional for an accurate diagnosis and appropriate treatment options.Additionally, any potential use of natural compounds in treating or preventing Alzheimer's disease would require extensive clinical research and validation.glucomoringin is believed to have anti-inflammatory properties [64][65][66] due to its potential to inhibit the production of inflammatory molecules in the body.Inflammation is a natural response to injury or infection, but chronic inflammation is associated with various health problems, including chronic diseases.Some studies suggest that moringa extracts, which contain glucomoringin, may help reduce inflammation in animal models [67].It is also considered an antioxidant.Antioxidants are compounds that help neutralize harmful free radicals in the body, which can cause oxidative stress and damage cells.By scavenging these free radicals, antioxidants can protect cells and tissues from damage.Moringa, with its various antioxidants, including glucomoringin, is thought to help combat oxidative stress [64,66].It is important to understand that while there is potential for health benefits associated with glucomoringin; more research is needed to establish its exact mechanisms of action and its efficacy in humans.Furthermore, the concentration of glucomoringin in moringa products can vary, so its effects may depend on the source and preparation.Despite the fact that the findings are encouraging, additional empirical research needs to be conducted in order to evaluate its efficiency and safety for certain applications.However, additional clinical tests are required to evaluate whether or not they are safe and whether or not they are successful in treating Alzheimer's disease.When contemplating alternative treatments, it is essential to work together with medical specialists in order to develop a care plan that is both comprehensive and risk-free.Because it has such a wide range of bioactivity, it is an attractive option for further research into medication development.

Future perspective
Advancements and challenges characterize research and treatment for Alzheimer's disease.Detecting the disease early is crucial, prompting current research to focus on accurate and accessible biomarkers for early-stage identification.Technologies such as neuroimaging, blood tests and wearable devices may aid in early diagnosis.The rise of personalized or precision medicine involves tailoring treatments to an individual's genetic and molecular profile, acknowledging Alzheimer's complexity and diverse causes.While current treatments manage symptoms, ongoing research aims to develop disease-modifying therapies targeting underlying causes like amyloid plaques and tau tangles to slow or halt progression.Combining various treatments, including drugs, lifestyle changes and alternative therapies, is under exploration for improved outcomes.Non-pharmacological interventions like cognitive training, exercise and diet gain attention for supporting cognitive health and delaying symptoms.Technology, such as digital health tools and telemedicine, is increasingly relevant in Alzheimer's care, offering remote monitoring, cognitive training apps and telehealth consultations.Collaboration among researchers, institutions and nations is vital for accelerating progress.Sharing data and findings helps identify trends and potential breakthroughs.The well-being of caregivers is a significant concern, emphasizing the need for support, education and resources.Future efforts should prioritize developing healthcare policies and systems to address the growing Alzheimer's burden, ensuring early diagnosis, affordable care and support for individuals and their families.Increasing public awareness and reducing Alzheimer's stigma are crucial for early diagnosis, research funding and supporting those affected by the condition.

Conclusion
The in silico evaluation of glucomoringin as a potential therapeutic agent for Alzheimer's disease presents promising findings.Molecular docking assessments indicate its potential as an anti-inflammatory agent, particularly in targeting interleukin-1β.The compound's pharmacokinetic properties, including favorable CNS permeability, warrant further investigation into appropriate dosing strategies.Importantly, glucomoringin demonstrates a favorable safety profile, making it a compelling candidate for further empirical research and potential therapeutic applications in Alzheimer's disease.While these in silico findings provide valuable insights, empirical studies are necessary to validate its efficacy and safety for clinical use.glucomoringin stands as a promising natural compound in the pursuit of novel treatments for Alzheimer's disease.As research in Alzheimer's disease continues to advance, these findings contribute to the growing body of knowledge aimed at developing effective treatments for this devastating condition.

Summary points
• The study suggests that glucomoringin has strong binding affinity to IL-1β, an inflammatory molecule associated with Alzheimer's disease.The pharmacokinetic analysis reveals important details about glucomoringin's properties, including its inhibition of specific cytochrome P450 enzymes and its clearance rate.These insights are crucial for understanding how the compound may interact with other drugs and how it is metabolized in the body.• The study underscores the significance of global collaboration in Alzheimer's research and the importance of personalized care for individuals with the disease.It emphasizes the complexity of Alzheimer's and the need for multifaceted approaches to treatment.• Glucomoringin demonstrates a favorable toxicological profile, with no indications of mutagenicity, carcinogenicity, irritant effects, or reproductive effects.This highlights its potential as a safe therapeutic option.• While the in silico findings are promising, the study emphasizes the importance of conducting empirical research to validate the efficacy and safety of glucomoringin for clinical use.• Glucomoringin exhibits a good bioactivity score in several key drug targets, such as GPCR ligands, ion channel modulators, kinase inhibitors and nuclear receptors.This versatility suggests its potential for modulating various biological pathways.• The study is part of the broader exploration of herbal treatments for Alzheimer's disease.It highlights the need for caution and the importance of consulting with healthcare professionals when considering alternative therapies.• Overall, the study offers promising insights into glucomoringin's potential as a therapeutic agent for Alzheimer's disease, but further empirical research is necessary to confirm its effectiveness and safety.
was written by C Manogna and all authors commented on previous versions of the manuscript.All authors read and approved the final manuscript.

Figure 1 .
Figure 1.Docking assessment of glucomoringin with multiple targets of Alzheimer.

Table 1 .
Docking assessment of glucomoringin on Alzheimer.

PDB ID Binding energy kcal/mol Conventional hydrogen bonding interaction
, increasing the property's security.The TPSA of a molecule is the ultimate determinant of how well a drug is absorbed.It also helps the medicine get where it needs to go.OSIRIS property explorer calculated the compound's Topological Polar Surface Area (TPSA) to be 281.77.The drug-likeness recorded for this molecule was -7.74.If the results are positive, it means that the molecule has parts that are commonly seen in commercially available drugs.You get its essence when you combine a drug's molecular weight, toxicity risks and cLogP.The medications' fundamentals are essential for figuring out if a given chemical can meet the needs of a treatment.The drug score of glucomoringin was found to be 0.3 and found that non-toxic compound (Green) in toxicity analysis using OSIRIS software.TPSA, drug-likeness, overall drug score was generated.
Toxicological prediction of glucomoringinThe toxicity of the investigated inhibitors was calculated using in silico methods.The physicochemical properties of the substance were determined with the help of OSIRIS Property Explorer.Exploring the glucomoringin toxicity profile before putting it through clinical trials is crucial.glucomoringin was shown to have no mutagenic, carcinogenic, irritant, or reproductive effects, according to the toxicity characteristics of the compounds tested.Most of the suggested inhibitors were found to have acceptable toxicity profiles, making them a viable therapy alternative.The OSIRIS property explorer granted the property a clean health bill concerning the aspects mentioned earlier
In silico & pharmacokinetic studies of glucomoringin from Moringa oleifera root for Alzheimer's disease like pathology Research Article Limitation Preliminary research findings form the basis for herbal treatments such as moringa and its alkaloids in addressing Alzheimer's disease.However, the efficacy and safety of these treatments remain uncertain, necessitating further clinical trials and research.Given the intricate nature of Alzheimer's disease with multiple contributing factors, it is crucial to acknowledge that there is no definitive cure.Treatment typically involves a combination of approaches, including medication, lifestyle adjustments and supportive care.It is imperative to discuss the use of herbal treatments with a healthcare professional due to variations in safety and efficacy based on individual health conditions, medications and other factors.Although herbal treatments show promise, they present challenges like inconsistent product quality, lack of standardized dosages and potential interactions with conventional medications.Rigorous clinical trials are indispensable for any treatment, including herbal remedies, to establish their safety and efficacy.Preliminary research findings should not be misconstrued as conclusive treatment options.Emphasizing the significance of consulting with a healthcare professional when considering Alzheimer's treatment is crucial.Self-medicating or relying solely on alternative therapies without medical guidance can pose risks.Alzheimer's disease lacks a one-size-fits-all treatment, underscoring the need for individualized care plans.Patients and their families should collaborate closely with healthcare providers to determine the most appropriate treatments and interventions.